Methods and apparatuses for reducing bleeding via coordinated trigeminal and vagal nerve stimulation

ABSTRACT

Disclosed are apparatuses and methods for reducing or limiting blood loss and reducing bleed time in a subject by combined vagus and trigeminal stimulation. The apparatuses and methods may activate (e.g., electrically) one or more branches of the trigeminal nerve and may concurrently (at overlapping or near-overlapping time) independently activate the vagus nerve. This activation may be invasive or non-invasive.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application claims priority to U.S. Provisional PatentApplication No. 62/736,447, filed on Sep. 25, 2018, and hereinincorporated by reference in its entirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference in their entirety to the sameextent as if each individual publication or patent application wasspecifically and individually indicated to be incorporated by reference.

FIELD

This disclosure is generally related to preventing and/or treatingbleeding in a subject. More specifically, this disclosure is related toapparatuses (devices, systems, and methods) for preventing and/ortreating bleeding and decreasing bleed time in a patient throughstimulation of both the trigeminal and vagus nerves, such as throughelectrical and/or mechanical stimulation of the trigeminal and vagalnerve.

BACKGROUND

Blood is an essential component of an animal's body to transport oxygen,nutrients and waste, protect the body with white blood cells and otherimmune system functions, and regulate body functions such as pH andhydration within critical ranges. Blood loss may lead to a variety ofproblems, including dysregulation or ultimately death. Blood loss canoccur due to a various causes. For example, there are approximately100,000,000 surgeries performed annually in the United States, withmillions more worldwide (CDC, National Center for Health Statistics) andthese generally have an inherent risk of bleeding, from minor topotentially life threatening. Aside from administration of tranexamicacid for select orthopedic procedures, there are no prophylacticsystemic therapies available to administer to help improve hemostasisand minimize surgical bleeding.

Trauma is the third leading cause of death in the United States (CDC,National Center for Health Statistics). A common cause of deathfollowing traumatic injury is uncontrolled bleeding (CDC, NationalCenter for Health Statistics). While modern tourniquets are sometimesavailable to help staunch hemorrhage following extremity trauma, theseinjuries are still dangerous. Approaches to control non-compressibletorso hemorrhage remain even more limited and this is a common cause ofdeath of U.S. soldiers on the battlefield.

Postpartum hemorrhage (PPH) is the leading cause of maternal deathsworldwide. The most common cause is poor contraction of the uterus.Other causes include uterine tears, retained placenta, and inadequateblood clotting. In the United States, approximately 11% of maternaldeaths result from PPH, whereas in the developing world approximately60% of maternal deaths result from PPH. This equates to 100,000 to140,000 deaths per year. Existing treatments include medications such asoxytocin, misoprostol, and ergotamine, intravenous fluids, bloodtransfusions, and uterine massage. Surgery to repair cervical or vaginallacerations or uterine rupture is sometimes necessary as well. Many ofthese therapeutic options are risky or unavailable in resource-poorareas, resulting in dramatically higher mortality rates.

Hemophilia A is an X-linked recessive disorder associated withspontaneous and prolonged bleeding episodes secondary to deficiencies inclotting factor VIII. More than 20,000 individuals in the United Statessuffer from this life-long disease. Up to 30% of children with severehemophilia cannot receive standard factor VIII concentrates due to thedevelopment of inhibitor antibodies. Maintaining hemostasis thenrequires bypassing agents, such as activated prothrombin complexconcentrate and recombinant factor VIIa, to help generate clot viaalternative pathways. These costly therapies are associated with serioussystemic thrombotic side effects, including myocardial ischemia, deepvenous thrombosis, and pulmonary embolism. Thus there is a need for newdevices, methods, and systems to prevent and treat bleeding problems.

Described herein are devices, methods, and systems that may address theissues identified above.

SUMMARY OF THE DISCLOSURE

The present invention relates to controlling bleeding in a patient. Morespecifically, this disclosure is related to apparatuses (devices,systems) and methods for controlling bleeding and bleed time in apatient through coordinated neural stimulation, such as throughelectrical and/or mechanical stimulation of both the trigeminal andvagal nerves. The apparatus may provide invasive or, preferably,non-invasive stimulation. The stimulation of the vagus nerve may beoverlapping, including concurrent, with the trigeminal never, or thetrigeminal nerve and vagus nerve may be alternately (with or withoutoverlap) stimulated. The same amount (one or more of: duration,frequency and/or intensity) of stimulation may be applied to both thevagus nerve and the trigeminal nerve, or the amounts (one or more of:duration, frequency and/or intensity) may be different. In somevariations Controlling bleeding may include preventing and/or treatingbleeding (e.g., surgical bleeding, traumatic bleeding, bleeding relatedto other medical procedures or conditions, and inherited or acquiredbleeding disorders).

For example, described herein methods of reducing bleed time in asubject that include: applying one or more of mechanical or electricalactivation to the subject's trigeminal nerve and the subject's vagusnerve; and reducing bleed time of the bleeding by at least 20%.

Also described herein are methods of reducing bleed time in a subjectthat has been treated with an anticoagulant, the method comprising:applying one or more of mechanical or electrical activation to thesubject's trigeminal nerve; and reducing bleed time of the bleeding byat least 20%.

A method of reducing or limiting blood loss in a hemorrhaging subjectmay include: applying one or more of mechanical or electrical activationto the subject's trigeminal nerve and the subject's vagus nerve; andreducing blood loss from the hemorrhage by at least 10%.

Also described herein are methods of treating a hemophiliac subject, themethod comprising: determining when the subject is bleeding; andapplying one or more of mechanical or electrical activation to thesubject's trigeminal nerve and the subject's vagus nerve to reduce theblood loss and/or bleeding volume.

In any of these methods, the mechanical and/or electrical stimulationmay be applied concurrently (e.g., at the same time), or overlapping intime (partially or completely overlapping) and/or within a few second(e.g., within 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, 6seconds, 10 seconds, etc.). In some variations the intensity of thevagus nerve stimulation may be less than the stimulation of thetrigeminal stimulation (e.g., x % or less, where x is 90%, 85%, 80%,75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or5% of the trigeminal stimulation). In some variations the intensity ofthe trigeminal nerve stimulation may be less than the stimulation of thevagus stimulation (e.g., x % or less, where x is 90%, 85%, 80%, 75%,70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%of the vagus stimulation). Specifically, the intensity may refer to oneor more of the applied voltage or current (e.g., when electrical energyis applied), and/or applied force or pressure (when mechanicalstimulation is applied). In some variations the intensity may refer tothe duration (e.g., the percentage of the total treatment time that thetrigeminal stimulation is active vs. the percentage of the totaltreatment time that the vagus stimulation is active). In some variationsintensity may refer to both the applied energy (voltage, force) and theduration of time energy is applied.

In any of these methods, applying may comprise non-invasively applyingone or more of mechanical or electrical activation. Although the methodsand apparatuses described herein typically refer to non-invasiveapplication of vagus and/or trigeminal stimulation, alternatively, inany of these methods applying may comprise applying from an implant(e.g., implanted neuromodulator that is in communication with thetrigeminal and/or vagus nerve).

In any of these methods, the subject may be human or non-human.

Applying may include applying one or more of mechanical or electricalactivation to one or more of an ophthalmic, maxillary and/or mandibularbranch of the subject's trigeminal nerve in addition to applying one ormore of mechanical or electrical activation to the vagus nerve. Forexample, applying may comprise applying one or more of mechanical orelectrical activation to sensory fibers of the patient's trigeminalnerve. In some variation, applying may be limited to applying via thesensory fibers. In some variations, applying comprises applyingunilateral activation to the subject's trigeminal nerve. Alternatively,applying may comprise applying bilateral activation to the subject'strigeminal nerve and/or vagus nerve.

Any of these methods may include reducing bleeding time. For example,reducing bleeding time may comprises reducing bleeding time from of oneor more of an internal hemorrhage or an external hemorrhage. Bleedingtime may be reduced (e.g., the application of electrical and/ormechanical energy may be applied until the bleeding time is reduced) bymore than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, etc.

Similarly, blood loss may be reduced (e.g., the application ofelectrical and/or mechanical energy which may be applied until the bloodloss is reduced) by more than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, etc.

Applying may comprise applying electrical stimulation to both the vagusnerve and the trigeminal nerve. For example, applying may compriseapplying electrical stimulation at between 1-50 Hz and between 0.5-15Vhaving a pulse width of between 0.5 ms and 10 ms to the trigeminal nerveand applying electrical stimulation of between 0.5-100 Hz and between0.2-15V having a pulse width of between 0.2 ms and 15 ms. Applying maycomprise applying for between 1 minute and 45 minutes. Applying maycomprise applying electrical stimulation to the trigeminal nerve andmechanical stimulation to the vagus nerve (e.g., in some variations, viathe auricular branch).

In any of these methods, applying may comprise applying withouttriggering a diver's reflex.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe claims that follow. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 schematically illustrates a system for stimulation both thetrigeminal nerve and the vagus nerve. In FIG. 1, the regions (e.g.,dermatomes) innervated by the trigeminal nerve are shown one or more ofwhich may be stimulated by the apparatus along with the vagus nerve,shown here schematically applying stimulation to the auricular branch ofthe vagus nerve.

FIGS. 2A-2H illustrate examples of stimulation patterns forsimultaneously stimulating both the vagus nerve and the trigeminalnerve.

FIGS. 3A-3D illustrate examples of systems that may be used tosimultaneously stimulate both the vagus nerve and the trigeminal nerveto reduce bleed time.

FIG. 4 is an example of a device for reducing bleed time bysimultaneously stimulating both the vagus nerve and the trigeminalnerve.

FIG. 5 schematically illustrates a system for reducing bleed time bysimultaneously stimulating both the vagus nerve and the trigeminalnerve.

DETAILED DESCRIPTION

The present invention relates to controlling (treating and/orpreventing) bleeding in a patient. More specifically, this disclosure isrelated to apparatuses (devices, systems, and methods) for controllingbleeding and controlling (reducing) bleed time in a patient throughneural stimulation, such as through electrical and/or mechanical and/orother stimulation of both (e.g., simultaneously) the trigeminal nerveand the vagus nerve. Controlling bleeding may include preventing and/ortreating bleeding (e.g., surgical bleeding, traumatic bleeding, bleedingrelated to childbirth, bleeding related to other medical procedures orconditions, bleeding mediated or increased by anticoagulants, inheritedor acquired bleeding disorders such as hemophilia, and so forth).

“Treatment” as used herein includes prophylactic and therapeutictreatment. “Prophylactic treatment” refers to treatment before onset ofa condition (e.g., bleeding, an inflammatory condition, etc.) ispresent, to prevent, inhibit or reduce its occurrence.

As used herein, a patient or subject may be any animal, preferably amammal, including a human, but can also be a companion animal (e.g., acat or dog), a farm animal (e.g., a cow, a goat, a horse, a sheep) or alaboratory animal (e.g., a guinea pig, a mouse, a rat), or any otheranimal.

“Bleed time” or “bleeding time” as used herein refers to the length oftime it takes to for bleeding to stop. In general, it is controlled orinfluenced by how well blood platelets work to form a platelet plug.Bleed time is generally increased by the administration ofanticoagulant, such as aspirin, heparin, and warfarin.

As used herein, the terms “reduce” or “reducing” when referring to bleedtime in a subject, encompass at least a small but measureable reductionin bleed time over non-treated controls. Reduction may be at least 5%,at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, or more than 60% or anything in between these ranges. Forexample, a value between these ranges may be chosen so as to use aprotocol or apparatus configured to reduce bleeding while minimizingside effects due to applied trigeminal and vagus nerve stimulation.

The nervous system controls nearly every cell and organ in the bodythrough electrical signals carried by nerves. Such electricalconnections allow the nervous system to monitor for tissue injury andthen to initiate a healing process. Described herein are apparatuses andmethods configured for harnessing such electrical connections viatargeted electrical nerve stimulation to effectively treat a variety ofconditions. Combined vagus and trigeminal nerve stimulation (VNS/TNS) asdescribed herein is a method to reduce bleeding or bleed time followingtissue injury or other bleeding event. Combined vagus and trigeminalnerve stimulation (VNS/TNS) as described herein may be non-invasive orminimally invasive. In some examples, VNS/TNS may be a non-invasive orminimally invasive method to activate the vagus nerve and previouslydescribed Neural Tourniquet. The combination of vagus nerve stimulationand trigeminal nerve stimulation may reduce the amount of one or bothvagus and trigeminal nerve stimulation necessary for robust reduction ofbleed time.

“Combined” vagus and trigeminal nerve stimulation (“VNS/TNS”) may referto the simultaneous (e.g., at the same time), overlapping ornear-overlapping (e.g., within about 10 seconds or less, e.g., within 9sec or less, 8 sec or less, 7 sec or less, 5 sec or less, 2 sec or less,1 second or less, 0.5 seconds or less, etc.) vagus and trigeminalstimulation.

“Non-invasive stimulation” typically means stimulation that does notrequire a surgery, exposure of the nerve fiber or direct contact withthe nerve fiber. As used herein, “non-invasive stimulation” also doesnot include administration of pharmacological agents. For example,non-invasive trigeminal nerve stimulation can be achieved, for example,by mechanical (e.g., vibration) or electrical (e.g. electromagneticradiation) means applied externally to the subject. Similarlynon-invasive vagus nerve stimulation may be achieved, for example, byelectrical or mechanical (e.g., vibration) stimulation appliedexternally (e.g., to the auricular region of the ear, over the auricularbranch of the vagus nerve.

Although in some examples, a non-invasive or minimally invasive approachas described herein may be used in conjunction with a pharmacologicalapproach (e.g., for an additive or a synergistic benefit), in general anapproach described herein may be more efficacious, safer, and lesscostly than traditional pharmacological therapies. Advantages of thismethod over pharmacological approaches may include higher specificity,fewer side effects, lower costs, and improved compliance. Advantagesover implantable pulse generators for chronic nerve stimulationapplications may include avoidance of surgery and associatedcomplications, both for the initial procedure and subsequent proceduresfor battery changes, and lower costs.

The trigeminal nerve (cranial nerve V) is the largest of the cranialnerves, and has three different branches or nerve distributions (V1, V2,V3; also referred to as the ophthalmic nerve, maxillary nerve andmandibular nerve, respectively) that converge on the trigeminalganglion. The trigeminal nerve is paired and present on both sides ofthe body. The trigeminal nerve relays sensory (and motor) informationfrom the head and face. Trigeminal nerve stimulation (TNS) is thought toactivate multiple structures in the brain and brainstem, such as thelocus coeruleus (LC) and nucleus tractus solitarius (NTS). FIG. 1 showsa schematic of the different skin regions corresponding to the differentbraches of the trigeminal nerve. The vagus nerve (cranial nerve X) isthe longest of the cranial nerves, extending from the brainstem downinto the peritoneal cavity. The vagus nerve is the main parasympatheticoutput of the autonomic nervous system, and interfaces with nearly everyorgan of the thorax and abdomen, including the heart, lungs, liver, andspleen. Vagus nerve stimulation (VNS) is clinically approved for thetreatment of medically refractory epilepsy and depression. Activation ofthe LC and NTS appears important to the antiepileptic effects of VNS. Todate, more than 100,000 patients have received VNS. Technologicaladvances may allow for nerve stimulation without surgical implantationof a pulse generator. For example, transcutaneous auricular stimulationdemonstrates anticonvulsive effects similar to invasive VNS.

Direct electrical stimulation of the cervical vagus nerve significantlyshortens the duration of bleeding and decreases total blood loss duringtissue trauma in swine. Rotational thromboelastography (RoTEG) revealedthat VNS significantly shortens the reaction (r) time of blood toinitiate clot formation. Moreover, VNS significantly increases thrombingeneration at the injury site, whereas systemic thrombin productionremains unchanged. Taken together, VNS improves hemostasis byaccelerating clot formation specifically at the site of tissue injury.

As described herein VNS/TNS (combined vagus and trigeminal stimulation)may include activating the trigeminal nerve (e.g., by electrical ormechanical or other stimulation) and activating the vagal nervedirectly. For example, the vagus nerve may be activated directly incombination with trigeminal nerve activation. Thus a step of controllingbleeding or activating the trigeminal nerve may include a step ofdirectly activating the vagal nerve. Activating the trigeminal nerve mayinclude activating the cholinergic anti-inflammatory pathway and/or anyother steps to control bleeding or bleed time in a subject as describedin U.S. Pat. No. 8,729,129, while concurrently directly stimulating thevagus nerve. The vagal nerve may be activated either directly orindirectly. In some particular examples, activating the vagusnerve-mediated reduced bleed-time safely and efficaciously may bethrough stimulation of the trigeminal nerve and the vagus nerve,utilizing precise and specific electrical stimulation parameters.Trigeminal nerve and vagus nerve stimulation may include improvinghemostasis via accelerated clot formation such as at the site of tissueinjury. This may lead to less blood loss and a shorter duration ofbleeding following tissue trauma and hemorrhage.

FIG. 1 shows one example of a schematic for a system configured for thecombined stimulation of the vagus and trigeminal nerves. In FIG. 1, thesystem may include a controller 101 that may include control logicand/or circuitry for driving combined stimulation of the vagus nerveusing a vagus nerve stimulation output 107 and a trigeminal nervestimulation output. In FIG. 1, the trigeminal nerve is shown with threealternatively stimulation outputs 105, 109, 113. One or more branch ofthe trigeminal nerve may be stimulated by the system; for example, inFIG. 1, the V1 branch of the trigeminal nerve may be mechanically orelectrically stimulated by a stimulation output 105 of the system. TheV2 branch of the trigeminal nerve may be mechanically or electricallystimulated by a stimulation output 113 of the system. The V3 branch ofthe trigeminal nerve may be mechanically or electrically stimulated by astimulation output 109 of the system. For example, one or moreelectrodes configured to contact the patient's skin over the V1, V2 orV3 branch of the trigeminal nerve may be included. Electricalstimulation may be applied (e.g., pulsed electrical stimulation ofbetween 1-4 kHz at a current of between 0.1 mA to 100 mA). Similarly,the system may include a vagus nerve stimulator 107 that may beconnected to the controller 101 to drive stimulation of the vagus nerve.The vagus nerve stimulation may be mechanical stimulator (e.g.,configured to apply mechanical force/pressure to the vagus nerve fromoutside of the body, e.g., by applying against the patient's ear) or anelectrical stimulator. For example, the electrical vagus nervestimulators may apply electrical stimulation from one or more electrodeson the surface of the patient's skin (e.g., the auricular region of theear). In some variations the electrode may be one or more tissuepenetrating electrodes (e.g., needles) inserted into the skin.

In either the vagus or trigeminal stimulators, the apparatus may includea patch (e.g., patch electrode) for contacting part of the body (e.g.,head, ear, face, etc.) of a subject and delivering a pulse and astimulator for providing an electrical stimulus to be delivered throughthe patch.

Any appropriate electrical or mechanical stimulation may be applied. Forexample, when applying electrical stimulation to the trigeminal nerve(e.g., through the face), a voltage stimuli (e.g., between 0.2 V to 5 V,at between 0.1-50 Hz, between 0.1 ms and 5 ms pulse width, monophasicand/or biphasic) may be applied for x min (e.g., where x is 2 min, 5min, 10 minutes, 20 minutes, or 30 minutes, etc.) duration. Vagus nervestimulation may be applied at approximately or exactly the same time.For example, one complete operational cycle (“dose”) may include a 0.2V-5 V monophasic pulses (e.g., sinusoidal, rectangular, etc. pulses) fora burst duration that is continuous or repeating, with pulses having aduration of between 0.1 ms and 10 ms (e.g., 2 milliseconds). This cyclemay be repeated at a repetition rate of between about 0.1 Hz and 1000 Hz(e.g., 30 Hz) for a treatment duration of between 1 min and 40 min(e.g., 10 minutes, 20 minutes, or 30 minutes, etc.). Concurrentlystimulation of the vagus nerve may be applied, e.g., through the ear.For example, stimulation of between about 0.1-10V, 0.1-10 mA, pulsed,e.g., rectangular pulses, for a burst duration that is continuous orrepeating, with pulses having a duration of between 0.1 ms and 10 ms(e.g., 2 milliseconds). This cycle may be repeated at a repetition rateof between about 0.1 Hz and 1000 Hz (e.g., 30 Hz) for a treatmentduration of between 1 min and 40 min (e.g., 10 minutes, 20 minutes, or30 minutes, etc.).

The pattern of concurrent stimulation for the vagus and the trigeminalmay be arranged in a variety of different ways. For example, FIGS. 2A-2Hillustrate variations of the combined vagus and trigeminal stimulation.In FIG. 2A, the vagus and trigeminal nerve are stimulated at the sametime (e.g., same start and stop). This simulation may be identical infrequency (e.g., puling, etc.), and/or intensity (e.g., amplitude, burstduration, etc.). For example, in variations in which both vagus andtrigeminal are stimulated electrically by pulsed electrical stimulation,the stimulation may occur at the same time, as shown (e.g., having thesame start/stop). Alternatively, in some variations combined vagus nerveand trigeminal nerve stimulation to reduce bleed time may include firststimulating the trigeminal nerve followed by stimulation of the vagusnerve, or by first stimulating the vagus nerve, followed by stimulationof the trigeminal nerve, as shown in FIG. 2A. This alternatingstimulation may be repeated for the entire dose duration. In FIG. 2Athere is no significant gap between the vagus stimulation and thetrigeminal stimulation; in some variations, as shown in FIG. 2D, thecombined vagus/trigeminal stimulation includes a gap 217 between thevagus and trigeminal nerve stimulation. As mentioned, this gap may beless than a few second (e.g., 10 seconds or less, 9 seconds or less, 8seconds or less, 7 seconds or less, 6 seconds or less, 5 seconds orless, 4 seconds or less, 3 seconds or less, 2 seconds or less, 1 secondsor less, 0.5 seconds or less, etc.). The vagus/trigeminal nervestimulation may therefore alternate and may be repeated for the entiredose duration.

Alternatively, in some variations, as shown in FIG. 2C, the combinedvagus and trigeminal stimulation may include overlapping 215 stimulationof the trigeminal and vagus nerve, as shown. In any of these variations,vagus nerve stimulation may begin before trigeminal nerve stimulation(as shown) or in some variations, trigeminal nerve stimulation may beginbefore vagus nerve stimulation.

In some variations, either vagus nerve stimulation or trigeminal nervestimulation may be intermittent and overlap with constant stimulation ofthe trigeminal (when vagus is intermittent) or vagus (when trigeminalstimulation is intermittent). In FIG. 2E the trigeminal nerve isstimulated continuously (although this may include pulsed or burst ofpulses) while the vagus nerve stimulation is intermittent (e.g., turned“on” and “off” with an intermittence frequency) during the doseduration.

In some variations, as shown in FIG. 2F-2H, combined vagus andtrigeminal nerve stimulation to reduce bleeding (e.g., reduce bleedtime) may include both vagus nerve stimulation and trigeminal nervestimulation being pulsed on/off at the same or different frequencies. InFIG. 2F, the vagus nerve stimulation may be performed at an on/offfrequency (intermittence frequency) that is different than thetrigeminal nerve stimulation frequency; in this example the vagus nervestimulation has a duty cycle of approximately 50%, while the trigeminalnerve stimulation has a duty cycle of >50% (e.g., >60%, approximately75%). The vagus nerve stimulation may partially overlap with thetrigeminal nerve stimulation during the dose duration, or may not.

In FIG. 2G the combined vagus and trigeminal stimulation to reducebleeding may include alternating periods of vagus and trigeminalstimulation in which either the vagus nerve stimulation is on for longerthan the trigeminal nerve stimulation or the trigeminal nervestimulation is on for longer than the vagus nerve stimulation (as shownin FIG. 2G). In FIG. 2H, both trigeminal and vagus nerve stimulation areon for the same duration, and the trigeminal and vagus nerve stimulation‘on’ times overlap.

In general, the non-invasive stimulation described herein may benon-invasive electrical stimulation applied at a predetermined range ofintensities and frequencies. However, other types of non-invasivestimulation may also be used (e.g. non-invasive mechanical stimulation)and can minimally invasive, subcutaneous stimulation. Non-invasivestimulation may be performed by one or more electrodes or actuators thatdo not contact the nerve. Electrical stimulation may be in the range of10 mV to 5 V at a frequency of 0.1 Hz to 100 Hz, with a duration ofstimulus between from 1 ms to 10 min.

Mechanical stimulation may be oscillatory, repeated, pulsatile, or thelike. In some variations the non-invasive stimulation may the repeatedapplication of a mechanical force against the subject's skin at apredetermined frequency for a predetermined period of time. For example,the non-invasive mechanical stimulation may be a mechanical stimulationwith a spectral range from 50 to 500 Hz, at an amplitude that rangesbetween 0.0001-5 mm displacement. The temporal characteristics of themechanical stimulation may be specific to the targeted disease. In somevariations the frequency of stimulation is varying or non-constant. Thefrequency may be varied between 50 and 500 Hz. In some variations thefrequency is constant. In general the frequency refers to the frequencyof the pulsatile stimulation within an “on period” of stimulation.Multiple stimulation periods may be separated by an “off period”extending for hours or even days, as mentioned above.

The force with which the mechanical stimulation is applied may also beconstant, or it may be variably. Varying the force and/or frequency maybe beneficial to ensure that the mechanical stimulation is effectiveduring the entire period of stimulation, particularly if the effect ofnon-invasive stimulation operates at least in part throughmechanoreceptors such as the rapidly acclimating Pacinian corpuscles.

In performing any of the therapies described herein, the non-invasivestimulation may be scheduled or timed in a specific manner. For example,a period of stimulation (“on stimulation”) may be followed by a periodduring which stimulation is not applied (“off period”). The off periodmay be much longer than the on period. For example, the off period maybe greater than an hour, greater than two hours, greater than fourhours, greater than 8 hours, greater than 12 hours, greater than 24hours, or greater than 2 days. The on period is the duration of astimulation (which may include a frequency component), and may be lessthan 10 minutes, less than 5 minutes, less than 2 minutes, less than 1minute, etc. The ratio of the on period and the off period may partiallydetermine the duty cycle of stimulation.

In some examples, either one (e.g., left or right) of the two pairedtrigeminal nerves may be activated (e.g., unilateral activation). Insome examples, the paired trigeminal nerves may be both be activated ina subject (e.g., bilateral activation). In some examples, part or all ofthe trigeminal nerve may be activated. For example, any one, two orthree of the three different branches or nerve distributions (V1, V2,V3; also referred to as the ophthalmic nerve, maxillary nerve andmandibular nerve, respectively) may be activated. In some examples,sensory fibers of the trigeminal nerve are stimulated. Additionally, thetrigeminal ganglion may also or instead be stimulated. Additionally orinstead, associated neurons that are connected to the trigeminal nervemay be stimulated.

Stimulation may be performed using one or more patches configured tocover part of the body each containing one or more electrodes (an arrayof 2, 3, 4, 5, 10, or more electrodes) configured to cover part of thebody (e.g. cheek, forehead, head, neck, nose, scalp, etc.) in a positionsufficient to provide stimulation one or more parts of a trigeminalnerve. Stimulation may be performed using one or more electrodesconfigured to be placed under the skin, such as in a muscle and 1, 2, 3,4, 5, 10, or more electrodes) may be placed in a muscle.

Also described herein are apparatuses (devices, systems, and methods)for activating the trigeminal nerve and the vagal nerve. In someembodiments, both the trigeminal nerve and the vagal nerve may bedirectly activated (e.g., by electrical, mechanical or other stimulationsuch as magnetic, thermal, etc.).

Further, in some variations, the trigeminal stimulation described hereinmay not activate the dive reflex. The dive reflex in general canactivated, for example, by submerging the body in cold water (andholding the breath) wherein the body overrides basic homeostaticfunctions. The dive reflex is a physiological adaptation that regulatesrespiration, heart rate, and arterial blood pressure in a particularway. Although all mammals control breathing, heart rate, and arterialblood pressure during their lives, these controls are strongly alteredduring diving and activation of the dive reflex. In general, trigeminalstimulation parameters may be chosen so as to not activate the divereflex (e.g., trigeminal stimulation without inducing a dive reflex).Failure to induce a dive reflex may be failure to invoke a percentagechange in heart rate and/or respiration and/or arterial blood pressureby more than a predetermined amount. For example, failure to induce adive reflex may be failure to reduce one or more of heart rate and/orrespiration and/or arterial blood pressure by greater than about 2%, 5%,7%, 10%, 15%, 20%, 25%, 30%, 40%, etc.

The apparatuses and methods described herein may be suitable fortherapeutically or prophylactically treating subjects suffering from orat risk from suffering from unwanted bleeding from any cause such as:bleeding disorders including but not limited to afibrinogenemia, FactorII deficiency, Factor VII deficiency, fibrin stabilizing factordeficiency, Hageman Factor deficiency, hemophilia A, hemophilia B,hereditary platelet function disorders (e.g., Alport syndrome,Bernard-Soulier Syndrome, Glanzmann thrombasthenia, gray plateletsyndrome, May-Hegglin anomaly, Scott syndrome, and Wiskott-Aldrichsyndrome), parahemophilia, Stuart Power Factor deficiency, vonWillebrand disease, thrombophilia, or acquired platelet disorders (suchas those caused by common drugs: antibiotics, and anesthetics, bloodthinners, and those caused by medical conditions such as: chronic kidneydisease, heart bypass surgery, and leukemia), childbirth, injury,menstruation, and surgery. An unwanted bleeding treated using any of theapparatuses or methods described herein may include an internalhemorrhage or an external hemorrhage. An internal hemorrhage includes ahemorrhage in which blood is lost from the vascular system inside thebody, such as into a body cavity or space. An external hemorrhageincludes blood loss outside the body.

EXAMPLES

FIG. 3A illustrates one example of a combined trigeminal and vagus nervestimulator for treating bleeding (e.g., for reducing bleed time) asdescribed. In FIG. 3A, the apparatus include a housing that isconfigured or adapted to fit over, behind and at least partially intothe patient's auricle region of the ear. The housing may include an earretainer 312 for holding the device in/on the ear 360, and may at leastpartially enclose a controller (e.g., control circuitry, a battery,power control circuitry, waveform generator, a trigeminal stimulationdrive and vagus stimulation drive). The apparatus also includes a vagusstimulator 307 that is coupled to the housing in this example, to beapplied against the patient's ear. A connector (e.g., cable, wire, etc.)connects a trigeminal stimulator 308 that may be worn on the patient'sface (e.g., in the V1, V2 and/or V3 region, as shown in FIG. 1). Thecontroller may be connected (via a wire or wireless connection) to auser interface that may control starting/stopping of the dose, or insome variations the housing may include a control (e.g., button, dial,etc.). The dose may be preprogrammed into the controller and/or it maybe adjusted.

FIG. 3B shows another example of a combined trigeminal and vagus nervestimulator for treating bleeding (e.g., for reducing bleed time) asdescribed. In FIG. 3B, the apparatus include a housing that isconfigured or adapted to fit at least partially into the patient's ear,as shown. The housing may be held in the ear 360, and may include a foamor other expandable material to help secure it in place. Alternatively aseparate retainer may be used to hold it in/on the ear (not shown). Thehousing may at least partially enclose a controller (e.g., controlcircuitry, a battery, power control circuitry, waveform generator, atrigeminal stimulation drive and vagus stimulation drive). The apparatusmay also include a vagus stimulator 307 that is coupled to the housingin this example, to be applied against the patient's ear. A connector(e.g., cable, wire, etc.) connects a trigeminal stimulator 308 that maybe worn on the patient's face (e.g., in the V1, V2 and/or V3 region, asshown in FIG. 1). The controller may be connected (via a wire orwireless connection) to a user interface that may controlstarting/stopping of the dose, or in some variations the housing mayinclude a control (e.g., button, dial, etc.). The dose may bepreprogrammed into the controller and/or it may be adjusted.

FIG. 3C is another example of a combined trigeminal and vagus nervestimulator for treating bleeding (e.g., for reducing bleed time) asdescribed. In FIG. 3C, the apparatus include an ear retainer 312 that isconfigured or adapted to fit at least partially over the patient's ear,as shown. The retainer holds the device over the patient's ear 360, sothat the vagus stimulator 307 is in contact with the region of the earover the vagus nerve. The retainer also holds the controller 302 and maybe formed of a material (e.g., mesh, etc.) that fits over the ear tohelp secure it in place. The controller (e.g., control circuitry, abattery, power control circuitry, waveform generator, a trigeminalstimulation drive and vagus stimulation drive) may be held by theretainer; the vagus nerve stimulator may include a biocompatibleadhesive (e.g., hydrogel, etc.) for making electrical contact with theear. A connector (e.g., cable, wire, etc.) connects the controller witha trigeminal stimulator 308 that may be worn on the patient's face(e.g., in the V1, V2 and/or V3 region, as shown in FIG. 1). Thecontroller may be connected (via a wire or wireless connection) to auser interface that may control starting/stopping of the dose, or insome variations the housing may include a control (e.g., button, dial,etc.). The dose may be preprogrammed into the controller and/or it maybe adjusted.

FIG. 3D is another example of a combined trigeminal and vagus nervestimulator for treating bleeding (e.g., for reducing bleed time) asdescribed. In FIG. 3D, the apparatus is configured or adapted to fit atleast partially into the patient's ear, as shown. The apparatus may beheld in the ear 360 by an ear retainer 312 to secure it in place. Theretainer may fit over the back of the ear and/or partially under the earto hold the apparatus in/on the ear. In FIG. 3D, the controller (e.g.,control circuitry, a battery, power control circuitry, waveformgenerator, a trigeminal stimulation drive and vagus stimulation drive)is shown on the front; in some variations the controller may be on theback of the apparatus (e.g., held behind the ear). The apparatus mayalso include a vagus stimulator 307 that is configured to contact theear. A connector (e.g., cable, wire, etc.) connects the controller to afirst trigeminal stimulator 308 that may be worn on the patient's face(e.g., in the V1, V2 and/or V3 region, as shown in FIG. 1). One or moreadditional trigeminal stimulators 308′ may be connected as well (e.g.,in parallel or in series with the first trigeminal stimulator). Thus,multiple sites may be used for trigeminal stimulation. The controllermay be connected (via a wire or wireless connection) to a user interfacethat may control starting/stopping of the dose, or in some variationsthe housing may include a control (e.g., button, dial, etc.). The dosemay be preprogrammed into the controller and/or it may be adjusted.

In any of these apparatuses, the vagus stimulator (vagus nervestimulator) may be an electrical or a mechanical stimulator. Invariations in which the apparatus is an electrical stimulator, the vagusstimulator may include one or more electrodes that may be coupled to thepatient's skin and/or may penetrate into the skin (e.g., as shallowneedle electrodes). The electrodes may apply electrical energy tomodulate the vagus nerve, as described herein. Mechanical stimulatorsmay apply mechanical energy as described above. Similarly, any of theseapparatuses may include one or more trigeminal stimulators that may beconfigured to apply electrical stimulation (e.g., including one or moreelectrodes, which may include a hydrogel for making skin contact). Thetrigeminal stimulators may alternatively be mechanical stimulators.

In any of the methods and apparatuses described herein, VNS/TNS canmodulate both the patient's sympathetic nervous system (SNS) andparasympathetic nervous system (PNS) activities to reduce bleed time.

As mentioned above, any of these methods and apparatuses may beconfigured to non-invasively applying neuromodulation of the trigeminalnerve and vagus nerve. Alternatively or additionally, invasive (e.g.,using a needle electrode, implant, etc.) may be used for either VNS, TNSor both VNS and TNS.

For example, non-invasive trigeminal stimulation may be applied via oneor more skin surface electrodes that apply trigeminal stimulation to oneor more of the subject's forehead, cheek(s), nose, tongue, or otherfacial skin. In some embodiments, applying the non-invasiveneurostimulation to the subject's trigeminal nerve includes targeting atleast one of the ophthalmic nerve, maxillary nerve, or mandibular nerve.Alternatively, in some variations, applying non-invasiveneurostimulation to the subject's trigeminal nerve includes avoidingtargeting at least one of the ophthalmic nerve, maxillary nerve, ormandibular nerve.

Any appropriate frequency and/or amplitude and/or duration may be used.In some embodiments, applying the non-invasive neurostimulation to thesubject's trigeminal nerve comprises non-invasive neurostimulation has afrequency of 1-300 (e.g., between 10-60 Hz, etc.). In some embodiments,the non-invasive neurostimulation has an intensity of 2 mV-20 V (e.g.,between 0.5 V and 15V, between 1 V and 12 V, etc.). In some embodiments,the non-invasive neurostimulation has a duty cycle of between about 20%to 70% (e.g., 1 second “on” and 1-2 seconds “off”). In some embodiments,the non-invasive neurostimulation includes a pulse width of betweenabout 0.1 ms to 10 ms (e.g., between about 0.1 ms to 5 ms, between about0.25 to 5 ms, etc.). In some embodiments, at least one of a stimulationvoltage or a current is increased gradually (e.g., steps of 0.1 V). Insome embodiments, the closed-loop trigeminal and/or vagus nervestimulation is conducted based on a heart rate of the patient (e.g.,subject). In some embodiments, the closed-loop trigeminal nervestimulation is conducted based on a heart rate variability (HRV) of thepatient. In some embodiments, certain parameters of the stimulation aremodulated to maintain values of the parameters within a target range(e.g., preventing a hear rate or blood pressure effect, etc.).

FIG. 4 is another example of a combined vagus and trigeminal nervestimulator for reducing bleeding (e.g., reducing bleed time). In FIG. 4,the apparatus includes a housing 401 enclosing a controller 402 (e.g.,control circuitry) and a battery 404. The housing is configured to fitbehind a patient's ear (not shown), and insert a vagus stimulator 407into the ear so that it is in contact with the region above theauricular branch of the vagus nerve. In FIG. 4 the apparatus alsoincludes an additional retainer 412 to help anchor the vagus stimulator.A trigeminal stimulator 408 is connected to the controller as well (theconnection shown in a wire). The trigeminal stimulator may be anelectrode pad that is in electrical communication with the controller(e.g., driver, waveform generator, etc.); similarly the vagus stimulatormay include an electrode (or electrode pad) that is in electricalcommunication with the controller.

FIG. 5 schematically illustrates some of the components of an apparatusfor combined vagus and trigeminal stimulation to reduce bleeding asdescribed above in FIGS. 3A-4. In the schematic of FIG. 5, thecontroller 502 may be separate from or integrated with one or moredrivers 510 and waveform generators 506 that may generate and providepower to the trigeminal stimulator (e.g., shown here as a trigeminalelectrode 508) and vagus stimulator (shown as a vagus electrode 507).The controller may also be connected to or include wirelesscommunication circuitry 514 for wirelessly communicating 522 with one ormore external devices 520 (shown in this example as a smartphone, thoughany external processor may be used). In FIG. 5, the controller(including control circuitry) may be housed within a housing 501. Insome variations this housing may be configured or adapted to fit into,on and/or over a patient's ear (generically referred to as on thepatient's ear).

When a feature or element is herein referred to as being “on” anotherfeature or element, it can be directly on the other feature or elementor intervening features and/or elements may also be present. Incontrast, when a feature or element is referred to as being “directlyon” another feature or element, there are no intervening features orelements present. It will also be understood that, when a feature orelement is referred to as being “connected”, “attached” or “coupled” toanother feature or element, it can be directly connected, attached orcoupled to the other feature or element or intervening features orelements may be present. In contrast, when a feature or element isreferred to as being “directly connected”, “directly attached” or“directly coupled” to another feature or element, there are nointervening features or elements present. Although described or shownwith respect to one embodiment, the features and elements so describedor shown can apply to other embodiments. It will also be appreciated bythose of skill in the art that references to a structure or feature thatis disposed “adjacent” another feature may have portions that overlap orunderlie the adjacent feature.

Terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention.For example, as used herein, the singular forms “a”, “an” and “the” areintended to include the plural forms as well, unless the context clearlyindicates otherwise. It will be further understood that the terms“comprises” and/or “comprising,” when used in this specification,specify the presence of stated features, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, steps, operations, elements, components, and/orgroups thereof. As used herein, the term “and/or” includes any and allcombinations of one or more of the associated listed items and may beabbreviated as “/”.

Spatially relative terms, such as “under”, “below”, “lower”, “over”,“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if a device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of over and under. The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly”, “downwardly”, “vertical”, “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

Although the terms “first” and “second” may be used herein to describevarious features/elements (including steps), these features/elementsshould not be limited by these terms, unless the context indicatesotherwise. These terms may be used to distinguish one feature/elementfrom another feature/element. Thus, a first feature/element discussedbelow could be termed a second feature/element, and similarly, a secondfeature/element discussed below could be termed a first feature/elementwithout departing from the teachings of the present invention.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising” means various components can be co-jointlyemployed in the methods and articles (e.g., compositions and apparatusesincluding device and methods). For example, the term “comprising” willbe understood to imply the inclusion of any stated elements or steps butnot the exclusion of any other elements or steps.

In general, any of the apparatuses and methods described herein shouldbe understood to be inclusive, but all or a sub-set of the componentsand/or steps may alternatively be exclusive, and may be expressed as“consisting of” or alternatively “consisting essentially of” the variouscomponents, steps, sub-components or sub-steps.

As used herein in the specification and claims, including as used in theexamples and unless otherwise expressly specified, all numbers may beread as if prefaced by the word “about” or “approximately,” even if theterm does not expressly appear. The phrase “about” or “approximately”may be used when describing magnitude and/or position to indicate thatthe value and/or position described is within a reasonable expectedrange of values and/or positions. For example, a numeric value may havea value that is +/−0.1% of the stated value (or range of values), +/−1%of the stated value (or range of values), +/−2% of the stated value (orrange of values), +/−5% of the stated value (or range of values), +/−10%of the stated value (or range of values), etc. Any numerical valuesgiven herein should also be understood to include about or approximatelythat value, unless the context indicates otherwise. For example, if thevalue “10” is disclosed, then “about 10” is also disclosed. Anynumerical range recited herein is intended to include all sub-rangessubsumed therein. It is also understood that when a value is disclosedthat “less than or equal to” the value, “greater than or equal to thevalue” and possible ranges between values are also disclosed, asappropriately understood by the skilled artisan. For example, if thevalue “X” is disclosed the “less than or equal to X” as well as “greaterthan or equal to X” (e.g., where X is a numerical value) is alsodisclosed. It is also understood that the throughout the application,data is provided in a number of different formats, and that this data,represents endpoints and starting points, and ranges for any combinationof the data points. For example, if a particular data point “10” and aparticular data point “15” are disclosed, it is understood that greaterthan, greater than or equal to, less than, less than or equal to, andequal to 10 and 15 are considered disclosed as well as between 10 and15. It is also understood that each unit between two particular unitsare also disclosed. For example, if 10 and 15 are disclosed, then 11,12, 13, and 14 are also disclosed.

Although various illustrative embodiments are described above, any of anumber of changes may be made to various embodiments without departingfrom the scope of the invention as described by the claims. For example,the order in which various described method steps are performed mayoften be changed in alternative embodiments, and in other alternativeembodiments one or more method steps may be skipped altogether. Optionalfeatures of various device and system embodiments may be included insome embodiments and not in others. Therefore, the foregoing descriptionis provided primarily for exemplary purposes and should not beinterpreted to limit the scope of the invention as it is set forth inthe claims.

The examples and illustrations included herein show, by way ofillustration and not of limitation, specific embodiments in which thesubject matter may be practiced. As mentioned, other embodiments may beutilized and derived there from, such that structural and logicalsubstitutions and changes may be made without departing from the scopeof this disclosure. Such embodiments of the inventive subject matter maybe referred to herein individually or collectively by the term“invention” merely for convenience and without intending to voluntarilylimit the scope of this application to any single invention or inventiveconcept, if more than one is, in fact, disclosed. Thus, althoughspecific embodiments have been illustrated and described herein, anyarrangement calculated to achieve the same purpose may be substitutedfor the specific embodiments shown. This disclosure is intended to coverany and all adaptations or variations of various embodiments.Combinations of the above embodiments, and other embodiments notspecifically described herein, will be apparent to those of skill in theart upon reviewing the above description.

What is claimed is:
 1. A method of reducing bleed time in a bleedingsubject by combined vagus nerve and trigeminal nerve stimulation, themethod comprising: applying one or more of mechanical or electricalactivation to the bleeding subject's trigeminal nerve and vagus nerve;and reducing bleed time of the bleeding subject by at least 20%.
 2. Themethod of claim 1, wherein applying comprises non-invasively applyingone or more of mechanical or electrical activation.
 3. The method ofclaim 1, wherein the bleeding subject is human.
 4. The method of claim1, wherein applying comprises applying one or more of mechanical orelectrical activation to one or more of an ophthalmic, maxillary and/ormandibular branch of the bleeding subject's trigeminal nerve andapplying stimulation to the auricular vagus nerve.
 5. The method ofclaim 1, wherein reducing bleeding time comprises reducing bleeding timeof one or more of an internal hemorrhage or an external hemorrhage. 6.The method of claim 1, wherein applying comprises applying electricalstimulation.
 7. The method of claim 1, wherein applying comprisesapplying electrical stimulation to both the vagus nerve and thetrigeminal nerve at between 1-50 Hz and between 0.5-15V having a pulsewidth of between 0.5 ms and 10 ms.
 8. The method of claim 1, whereinapplying comprises applying for between 1 minute and 45 minutes.
 9. Amethod of reducing or limiting blood loss in a hemorrhaging subject themethod comprising: applying one or more of mechanical or electricalactivation to the hemorrhaging subject's trigeminal nerve; concurrentlyapplying one or more of mechanical or electrical activation to thehemorrhaging subject's vagus nerve; and reducing blood loss from thehemorrhage by at least 10%.
 10. The method of claim 9, wherein applyingcomprises non-invasively applying one or more of mechanical orelectrical activation.
 11. The method of claim 9, wherein applying oneor more of mechanical or electrical activation comprises applyingelectrical stimulation.
 12. The method of claim 9, wherein applying oneor more of mechanical or electrical activation comprises applyingelectrical stimulation to both the vagus nerve and the trigeminal nerveat between 1-50 Hz and between 0.5-15V having a pulse width of between0.5 ms and 10 ms.
 13. The method of claim 9, wherein applying one ormore of mechanical or electrical activation to the hemorrhagingsubject's trigeminal nerve comprises applying for between 1 minute and45 minutes.
 14. A method of treating a hemophiliac subject by combinedtrigeminal and vagus nerve stimulation, the method comprising:determining when the subject is bleeding; and applying one or more ofmechanical or electrical activation to the subject's trigeminal nerveand the subject's vagus nerve to reduce the blood loss and/or bleedingvolume.
 15. The method of claim 14, wherein applying one or more ofmechanical or electrical activation comprises non-invasively applyingone or more of mechanical or electrical activation.
 16. The method ofclaim 14, wherein applying one or more of mechanical or electricalactivation comprises applying electrical stimulation.
 17. The method ofclaim 14, wherein applying one or more of mechanical or electricalactivation comprises applying electrical stimulation to both thesubject's vagus nerve and the subject's trigeminal nerve at between 1-50Hz and between 0.5-15V having a pulse width of between 0.5 ms and 10 ms.18. The method of claim 14, wherein applying one or more of mechanicalor electrical activation to the subject's trigeminal nerve and thesubject's vagus nerve comprises applying for between 1 minute and 45minutes.
 19. A method of reducing bleed time in a subject that has beentreated with an anticoagulant by combined trigeminal and vagus nervestimulation, the method comprising: applying one or more of mechanicalor electrical activation to the subject's trigeminal nerve after thesubject has been treated with the anticoagulant; concurrently applyingone or more of mechanical or electrical activation to the subject'svagus nerve; and reducing bleed time of the bleeding by at least 20%.